title: Stress rapidly dysregulates the glutamatergic synapse in the prefrontal cortex of cocaine-withdrawn adolescent rats.
abstract: Although several lines of evidence have shown that chronic cocaine use is associated with stress system dysregulation, the underlying neurochemical mechanisms are still elusive. To investigate whether the rapid stress-induced response of the glutamatergic synapse was influenced by a previous history of cocaine, rats were exposed to repeated cocaine injections during adolescence [from postnatal day (PND) 28-42], subjected to a single swim stress (5 minutes) three days later (PND 45) and sacrificed 15 minutes after the end of this stressor. Critical determinants of glutamatergic homeostasis were measured in the medial prefrontal cortex (mPFC) whereas circulating corticosterone levels were measured in the plasma. Exposure to stress in saline-treated animals did not show changes in the crucial determinants of the glutamatergic synapse. Conversely, in cocaine-treated animals, stress dynamically altered the glutamatergic synapse by: (1) enhancing the presynaptic vesicular mediators of glutamate release; (2) reducing the transporters responsible for glutamate clearance; (3) increasing the postsynaptic responsiveness of the N-methyl-D-aspartate subunit GluN1; and (4) causing hyperresponsive spines as evidenced by increased activation of the postsynaptic cdc42-Pak pathway. These findings indicate that exposure to cocaine during adolescence sensitizes mPFC glutamatergic synapses to stress. It is suggested that changes in glutamatergic signaling may contribute to the increased sensitivity to stress observed in cocaine users. Moreover, glutamatergic processes may play an important role in stress-induced reinstatement of cocaine seeking.
authors.affiliation: Centro di Neurofarmacologia, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy; Collaborative Center of Department of Antidrug Policies, Presidency of the Council of Ministers, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Caffino
authors.forename: Francesca
authors.initials: F
authors.lastname: Calabrese
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannotti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barbon
authors.forename: Michel M M
authors.initials: MM
authors.lastname: Verheij
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Fabio
authors.initials: F
authors.lastname: Fumagalli
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D027341:Excitatory Amino Acid Transporter 1 / Q000187:drug effects / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism*; D013550:Swimming; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D003042:Cocaine; D003345:Corticosterone; D018765:Dopamine Uptake Inhibitors; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2
keywords: Adolescence; cocaine; glia; glutamate; prefrontal cortex; stress